25 



for eventual advancement to clinical trials with human patients. The various stages of 

 preclinical development are: 



1 . Large-scale production of the active agents through large-scale recollections of 

 the source raw material from the original site of collection, or through 

 cultivation of plants or aquaculture of marine organisms. 



2. Formulation studies to develop suitable vehicles to solubilize the drug to enable 

 administration to patients. 



3. Pharmacological evaluation involving the study of various drug parameters 

 (bioavailability in blood and plasma, rates and routes of clearance, and 

 metabolism) in suitable animal models. 



4. Toxicological evaluation of the drug to determine the type and degree of major 

 toxicities in animal (rodents, dogs) models and safe starting doses for clinical 

 trials in humans. 



On completion of preclinical studies and favorable review by the NCI staff, all the necessary 

 data are collated and submitted to the FDA as an Investigational New Drug Application 

 (INDA). Once the FDA has approved an INDA, the various phases of clinical development 

 may begin. Initial studies, also known as Phase 1 trials, are conducted in patients to 

 determine the maximum tolerated dose of the drug in humans, and to observe the sites and 

 reversibility of toxic effects. Once the maximum tolerated dose has been determined, and 

 NCI staff are satisfied that no insurmountable problems exist with toxicities, the drug 

 advances to Phase II clinical trials which are conducted to test the efficacy of the drug in 

 patients with a range of different types of cancer or those with HIV infection and its 

 sequelae. For drugs demonstrating beneficial effects in the Phase II trials. Phase III clinical 

 trials are conducted against those disease-types responding to the new drug treatment, and the 

 efficacy of the drug is compared with that of the best chemotherapeutic agents currently 

 available. In addition, the new drug may be tried in combination with other effective agents 

 to determine if the efficacy of the combined regimen exceeds that of the individual drugs 

 used alone. 



Since the NCI does not market drugs, collaborations with pharmaceutical companies are 

 developed at the stage of human clinical evaluation and, if possible, even earlier in 

 development. Once sufficient evidence has been accumulated, frequently by both the 

 company and NCI, indicating that the new drug is effective for a particular disease, all the 

 necessary information is assembled and the company then files a New Drug Application 

 (NDA) with the FDA. The NDA generally will apply only to the particular responsive 

 disease-type, and approval by the FDA usually permits marketing of the drug only for use in 

 the treatment of that disease-type. 



Since the passage of the Stevenson-Wydler Technology Innovation Act of 1980 and the 

 Federal Technology Transfer Act of 1986, it is a national policy to transfer federally-owned 

 or originated technology to the private sector whenever appropriate. The Act also 

 encouraged, as a national policy, joint research and development projects between 



